Hydrogels Allow Sustained Release of siRNAs

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Scientists have developed a targeted delivery and controlled release system for small interfering RNAs (siRNAs) based on polymer-linked biodegradeable hydrogels. The researchers, at Case Western Reserve University’s department of biomedical engineering and orthopedic surgery, hope the technology will facilitate the use of siRNAs for therapeutic applications in fields ranging from tissue regeneration to cancer therapy.

The biggest limitation to using RNA interference in a clinical setting is delivery, both in terms of localizing the molecules to a specific cell population and also effecting sustained release of the tiny siRNA molecules. The technology developed by Case Western’s Eben Alsberg, Nhanh Nguyen, and Phuong Ngoc Dang, involves packaging the siRNAs into dextran hydrogels cross-linked with the transfection agent linear polyethyleneimine (LPEI). The key ingredient is the PEI polymer, which interacts with the siRNA, effectively holding the double-stranded oligonucleotides in the hydrogel until the covalent ester linkages between the LPEI and hydrogels gradually degrade. The release profile can be varied simply by changing the relative concentrations of dextran and LPEI.

Initial tests by the researchers showed that covalently conjugating the LPEI to the dextran had no effect on the swelling or degradation properties of the hydrogels, while the addition of siRNA and LPEI to the dextran had a minimal effect on mechanical properties. Moreover, they report, the hydrogels exhibited low cytotoxicity to human embryonic kidney cells. And importantly, the siRNAs retained bioactivity over long periods of time.

The Case Western team reports its developments in Acta Biomaterialia, in a paper titled “Functionalized, biodegradable hydrogels for control over sustained and localized siRNA delivery to incorporated and surrounding cells.” Dr. Alberg has been awarded a $346,000 NIH grant to evaluate use of the technology for growing bone and cartilage from stem cells.